DESCRIPTION: (Applicant's Abstract) While recent epidemiological studies suggest that the prevalence of illicit cocaine use has plateaued over the past few years, cocaine abuse continues to pose a significant public health problem in the United States. Despite a vigorous research effort directed towards developing an effective medication, no pharmacotherapies to date have well demonstrated clinical efficacy against cocaine abuse. This project proposes to evaluate the potential efficacy of kappa-opioid compounds to alter the euphorigenic effects of cocaine and to reduce cocaine use. There is a substantial amount of preclinical evidence which suggests that compounds with kappa-opioid activity can decrease the neurochemical, behavioral, and reinforcing effects of cocaine. A series of four controlled laboratory studies are proposed that will systematically evaluate the safety and efficacy of two kappa agonists in humans when given alone and in combination with cocaine. Enadoline, a novel agent which acts selectively at kappa sites as a full agonist, and butorphanol, an agent with mixed opioid activity which acts as a partial agonist at kappa sites, will be tested. An initial within-subject dose-ranging study will evaluate and compare the safety and pharmacodynamic profiles of enadoline and butorphanol over a range of doses. The second study will evaluate and compare the effects of enadoline and butorphanol when administered under acute dosing conditions in combination with cocaine in an effort to determine the safety of concomitant administration of these agents. This within-subject study will also assess the ability of enadoline and butorphanol to alter the subjective response to intravenous cocaine and cocaine self-administration, as an index of their potential efficacy for reducing cocaine use. The third and fourth studies will evaluate the safety of chronic treatment with enadoline and butorphanol, respectively, characterize the tolerance that develops following chronic administration of these drugs, and evaluate their ability to alter cocaine self-administration and the pharmacodynamic effects of cocaine during chronic dosing. These studies will contribute importantly to our understanding of the interaction between cocaine and kappa opioids in humans and will systematically evaluate this class of drugs for their potential efficacy against cocaine abuse. These studies are relevant to the treatment of cocaine abuse and may lead to the development of an effective pharmacotherapy, thereby, reducing the HIV and other health risks associated with cocaine abuse and intravenous drug abuse.